Dihydropyrrolo-(3.2-c) quinoline derivatives



Patented Oct. 5, 1954 DIHYDROPYRROLO- 3.2-) QUINOLINE DERIVATIVES HanssUlrich Hiirlein, Hans Andersag, and Helmut TimmleraWuDPfltal-Elberfeld, Germany, assignorsstossclienly lndustries, Inc., New York, N.".,YI a corppratlon of Delaware N Drawing-e. ApplicationApriLZB,195:3 Serial'No; 35117511 Claims? priority; applica tfon Germany May 26, 19522;

24 Claims. 01.1260L-28831 Thisinventioir=relateszgenerallyrtwtheasyntlree sis: oi? organic: chemical compounds; and; more particularlyyitmelatesto.tcertain mvekiderivatives of 4-methyl-2,3-dihydro pumice-(39am) qmnos line useful in chemotherapy especially in treatment of malaria andamoebiasisr The novel compounds of this invention. are represented by the formula:

wherein@Rtnisnohosen';fromztheegroumconsistlng of; hydrogen; methyl,.. dimethylaminoethwls 61+ ethylannnoethyhandrbenzxt; "andRaaRae =Rls8zfld Rs :are: chosen zfrom @thevgg'oup; consisting; of; hy; Grog-en: anduati most; twmmembern chosem from the? group,- comisting; of; m droxy i methoxn, ethnxyr, Ne'methylcarhamyli and"; chlorine.-, The compounds;orithe:foreso flflizformulaswherem4R1 isz psdiethylaminoethnl,-, Rm. is methoxy;, and: Re;

C HaCHzX X: halo ene t R=hydiogen, alk'yl, arylal yr: dYa-lkylaminoalkyl.

It rise preferred& that ,the reaetionr-rbes performed imatsuitahle normally yliquidpriowmelting solid, semipolarrorganie, solvent such. assan BJOOhOhOU aiphenola Ammonia-- or low.- boiling ppinttannnes can be .introduoedzintothezhot'reac-r tion-t mixture; while a in; thee gaseousn state f and hiazherboilinnnpint aminesmay bes-addedsduring onbeforeu-themeatinge If iammoniaiissusedlasta primary; reactant and derivatives substituted :at utlael-position pyrroloe nitrogen atom iareydesiredas-therfinaLpr-oducts; theecompoundsswh-ich are unsubstituted at the pyrrolo-nitrogen atom can be converted intoaN-tsodium, potassium, lithium.-or magnesium compounds by treatment with metallic sodium, potassium; or--lithium,' or-a Grignardreagentr The N-metallo compounds can then be convertedto the desired products-by-treatment with reactive esters, for instance, aliphatic halides, araliphatic halides, or hydroxyowamino-substituted aliphatic alcohols.

In the following examples wherein the preparation of certainspecificproducts of this invention is described, the primary reactants employed are: (1) ammonia or a primary. amine, mambe wshort -chain" amino alI'r-ane; such as: methyl amine; an NgNshort-cliain dialkyl diam-i no axlkanw such' as NgN -dimethyl ethyl-ene diamine or' N'EN- diethyl ethylne-diaminey or a simple aralkvlaminw such as i benzylaminer and (2) a=3'- ,9==cliloroet1 iyl- 4=-chloro=quinaldinee which may be devoid o bz substituents on Which-- may bean aS*fiZ-*5l1b'SbitlImS-OHBOFIRQEB IOWQI allrox-y radicals. (e: gt; methoxy," ethoxy); hydroxyl groups, or N-'mom:rlower alk y l-earloamyil (e g2, N-methyl-carbamylh These quinaldine, primary reactants may be preparedasfollows: Anilineor*arsulostitnted a-niline, selected to provide whatever bz-substituent group or groups that-may -hezdesired in the final product, is condensed with a-aceto-v-butyrolactone to form a Schifiis base/type compound represented by the general formula:

phorus oxychloride, the products obtained are 3- p-chloroethyl-4-chloro-quinaldines which, if a substituted aniline is used in their preparation, will be substituted likewise in the bz-nucleus.

To facilitate a better understanding of this invention, the following examples are suppliedby way of illustration, merely, not by way of limitation uponthe scope of the invention.

Example 1 Synthesis of the compound represented by the formula:

About 100 parts by weight of 3-,8-chloroethy1- 4-chloro-quinaldine are melted with 100 parts by weight of phenol and a stream of ammoniais passed into the melt, which is heated gradually to 155-160 C. The ensuing exothermic reaction causes the temperature to rise to about 180200 C. When the reaction has slowed down, the mass is heated further at 160-170" C. for about one-half to one. hour, cooled, then treated with 2-N sodium hydroxide solution and filtered under suction. pyrrolo-(3.2-c)quinoline thus obtained asthe filtration residue is dissolved in dilute acetic acid, reprecipitated by addition of aqueous sodium hydroxide solution, and recrystallized from a mixture of ethanol and petroleum ether or from pyridine. The thus-purified compound has a melting point higher than 270 C. and it is obtained in an amount of about 65% of the theoretical.

Example 2 Synthesis of the compound represented by the formula:

Example 3 Synthesis of the compound represented by the formula:

The crude 4-methyl-2,3dihydro- 4 there employed. The product so obtained is 1,4- dimethyl-2,3-dihydropyrrolo (3.2 c) quinoline, melting at 108 C. and boiling at 190 C. under a pressure of 0.2 millimeter of mercury.

Example 4 Synthesis of the compound represented by the formula:

The procedure described in Example 2 is repeated I point,. 102 C.) replacing the 3-p-chloroethyl-4- chloroQk-methoxy-quinaldine there employed.

The product so obtained is 1,4-dimethyl-7-methl oxy 2,3 dihydropyrrolo-(3.2-c) quinoline, melt- The procedure described in Example 2 is repeated with an equimolecular proportion of 3-5-chloroethyl-4-chloroquinaldine replacing the 3-,3 chloroethyl-4-ch1oro 8 methoxy quinaldine ing at 142-143 C. and boiling at 220-230 C. at a pressure of 0.3 millimeter of mercury. 1,4-dimethyl-'l-hydroxy-2,3-dihydropyrrolo (3.2-0)- quinoline can be obtained by heating the 7-methoxy compound with hydrobromic acid (specific gravity, 1.5) and its hydrobromide salt melts higher than 300 C.

Ezcample 5 Synthesis of the compound represented by the formula: I

H3C--N The procedure described in Example 2 is repeated with an equimolecular proportion of 3-5- chloroethyl-4-chloro 6 methoxyquinaldine (melting point, 121 C.) replacing the 3-fi-chloroethyl-4-chloro-B-methoxy-quinaldine there employed. The product so obtained is 1,4-dimethyl- 8 methoxy-2,3-dihydropyrrolo=(3.2-c) quinoline, melting at 82-83 C. and boiling at 220-230" C. at a'pres'sure of 0.3 millimeter of mercury. 1,4-dimethyl-8-hydroxy2,3-dihydropyrrolo (3.2-0)- quinoline can be obtained by heating the B-meth- 'oxy compound with hydrobromic acid (specific gravity, 1.5) and its hydrobromide salt melts higher than 300 C., after crystallizing from hot formamide.

Example 6 Synthesisof the compound represented by the formula:

' HaC-N N CH: )0111! sure of 0.2 millimeter of mercury.

Earample 7 Synthesis of the compound represented by the formula:

HsGN

N, CH:

The procedure described in Example 21s repeated with an equimolecular proportion of 3-p-chloroethyl 4 chloro 6 ethoxy-quinaldine (melting point, 118 C.) replacing the 3-,3-chloro-ethyl- 4-chloro-8-methoxy-quiiialdine there employed. The product so obtained is 1,4-dimethyl-8-ethoxy- 2,3-dihydro-pyrrolo-(3.2-)quinoline, melting at 82, C. and boiling at 224-234 C. at a pressure of 0.2 millimeter of mercury.

The procedure described in Example 2 is repeated with an equimolecular proportion of 3-fi-chloroethyl 4 chloro 6 N methylcarbamylquinaldine replacing the 3 ,8 chloroethyl 4- chloro 8 methoxy quinaldine there employed. The product so obtained is 1,4-dimethyl-8-N- methylcarbamyl 2,3 dihydropyrrolo (3.2 c) qumoline, melting at 229-230" C.

Example 9 Synthesis of the compound represented by the formula:

N CH:

CzHt

About 35 grams of 3-5-chloroethyl-4-chloro- 8-ethoxy-quina1dine (melting point, 119 C.) are heated with 35 grams of phenol and 70 grams of benzylamine for three hours at 1'70-180 C. After cooling, the reaction mixture is introduced into 2-N sodium hydroxide solution and the phenol is dissolved. The undissolved, crude, 1- benzyl 4 methyl 6 ethoxy 2,3 dihydropyrrolo-(3.2-c)quino1ine is filtered off. under suction, dissolved in dilute acetic acid, and reprecipitated by addition of sodium hydroxide solution; After drying, it is extracted with ligroin in a Soxlet extractor, the ligroin distilled off, and the residue is dissolved in ethyl acetate. By adding maleic acid to the ethyl acetate solution, the maleate of 1-benzyl-4-methyl-6-ethoxy-2,3- dihydropyrrolo (3.2 c) quinoline is obtained, which melts at 177 0., after being recrystallized 6 from a mixture of ethylalcohol and ethyl acetate.

: Example 10 I Synthesis of the compound represented by the formula:

About 40 grams of 3-,8-chloroethyl-4-chloroe7- methoxy-quinaldine (melting point, 102 C), 40 grams of phenol and 7-0 grams of s-diethyl'aminoethylamine'are refluxed for three hours. The reaction product is dissolved in methylene chloride and the solution so obtained is extracted, first, with dilute sodium hydroxide solution, then with water, to remove the phenol. The methylene chloride solution is dried over solid potassium carbonate and distilled. The l-s-diethylaminoethyl -'4 methyl 7 methoxy 2,3 dihydropyrrolo-(3.2-c)quinoline distills over at 228-237 C. at a pressure of 0.1 millimeter of mercury. The distillate is taken up in acetone and the hydrochloride of 1- 8diethylaminoethyl-i-methyl- 7 methoxy 2,3 dihydropyrrolo (3.2 c) quinoline precipitated by hydrochloric acid. After recrystallization from a mixture of alcohol and ether, the purified product melts at 265 C. and is obtained in a yield of about 32% of the theoretical. Better yields are obtained if the excess of B-diethylamino-ethylamine is reduced. 1 However, by boiling the reaction mixture for 15 hours, the methoxy group is partly attacked by hydrochloric acid, formed as a by-product during the reaction, and about equal parts of the methoxy compound and of l fi diethylamlnoethyl 4- methyl 7 hydroxy 2,3 dihydropyrrolo- -(3.2-c)quinoline are obtained. By reacting the mixture with hydrobromic acid (specific gravity, 1.5), the methyl group can be completely split off, giving essentially complete conversion of the 7-methoxy to the 7-hydroxy compound. The naphthalene 1,5 disulfonate of 7 hydroxy 4- methyl 9 1 fl diethylaminoethyl 4- methyl 7 hydroxy 2,3 dihydropyrrolo- (3.2-c)quinoline melts higher than 285 C.

Emample 11 Synthesis of the compound represented by the formula:

Emample 12 Synthesis of the compound represented by the formula:

N OH:

OCH:

Example 13 Synthesis of the compound represented by the formula:

The procedure described in Example is repeated with an equimolecular proportion of 9- chloroethyl 4 chloro 8 hydroxy quinaldine (melting point, 180 C.) replacing the 3-fl-chloroethyl-4-chloro-7-methoxy-quinaldine there employed. The product so obtained is l-p-diethylaminoethyl 4 methyl 6 hydroxy 2,3 dihydropyrrolo-(3.2-c)quinoline, which yields a naphthalene-1,5-disulfonate salt melting at over 300 C.

Example 14 Synthesis of the compound represented by the formula:

The procedure described in Example 10 is repeated with 3-5-chloroethyl-4-chloro-6-methoxyquinaldine (melting point, 121 C.) replacing the 3 fl chloroethyl 4 chloro 7 methoxy quinaldine there employed. The product so obtained is 1 B diethylamino 4 methyl 8 methoxy 2,3 dihydropyrrolo (3.2 c)quinoline, which yields a maleate salt that melts at 155 C.

Easample 15 Synthesis of the compound represented by the formula:

(C2135) 2N. czHnTj 'The procedure described in Example 10 is repeated with 3-fi-chloroethyl-4,6-dichloro-quinaldine (melting point 117 C.) replacing the 3-}8- chloroethyl 4 chloro 7 methoxy quinaldine there employed. The product so obtained is 1-49- diethylaminoethyl 4 methyl 8 chloro 2,3 dihydropyrrolo-(3.2-c) quinoline, which yields a hydrochloride salt melting at above 300 C.

Example 16 Synthesis of the compound represented by the formula:

The procedure described in Example 10 is repeated with 3 ,9 chloroethyl 4,5 dichloro 8-methoxy-quinaldine replacing the 3-fi-chloroethyl-4-chloro-'l-methoxy-quinaldine there employed. The product so obtained is l-B-diethylaminoethyl 4 methyl 6 methoxy 9 chloro 2,3 dihydropyrrolo (3.2 c)quinoline, which, after being recrystallized from ligroin. melts at 108-109 C.

Example 17 Synthesis of the compound represented by the formula:

The procedure described in Example 10 is repeated with 3 ,8 chloroethyl 4 chloro 6,7 dimethoxy-quinaldine replacing th 3-fi-chloroethyl-4-chloro-'7-methoxy-quinaldine there employed. The product so obtained is l-p-diethylaminoethyl 4 methyl 7,8 dimethoxy 2,3 dihydropyrrolo-(3.2-c) quinoline, which yields a naphthalene-1,5-disulfonic acid salt melting at above 300' C.

Example 18 Synthesis of the compound represented by the formula:

1 N/ OH:

OCH: About 50 grams of 3-fi-chloroethyl-4-chloro-8- methoxy-quinaldine are melted with 50 grams of phenol and ammonia is introduced into the melt at ISO-180 C. After one hour, the mixture is cooled and stirred with dilute sodium hydroxide solution. The insoluble residue comprising crude 4 methyl 6 methoxy 2,3 dihydropyrrolo (3.2-c)quinoline is dissolved in dilute acetic acid and reprecipitated by addition of dilute sodium hydroxide solution. The product is removed, stirred with alcohol, then the alcohol is removed by suction filtration and the residue is dried. The crude compound so obtained can be subjected to basic alkylation or may b purified in substan- 9 tially the same manner as the products obtained as described in the foregoing examples.

Example 19 Synthesis of the compound represented by the formula:

(CH3)2N.C2H4.N

( )CHa About 16 grams of crude 4-methyl-6-methoxy- 2,3-dihydropyrrolo-(3.2-c)quinoline, which may be obtained as described in Example 18, are boiled for 2 hours in 150 cubic centimeters of dried xylene with 5 grams of sodamide moistened with toluene. Thereupon, a solution of 10 grams of B-dimethylaminoethyl chloride in xylene is added, drop by drop, and the mixture is allowed to boil for another two hours. After cooling, the precipitate is removed by filtration under suction, washed with xylene, and the xylene filtrate and washings are shaken several times with aqueous dilute acetic acid. Crude l-fi-dimethylaminoethyl 4 methyl 6 methoxy 2,3 dihydropyrrolo-(3.2-c) quinoline can be recovered from the acetic acid solution 'by precipitation following addition of sodium hydroxide solution. The precipitate is removed by vacuum filtration, washed with water, and dried. The dried substance is dissolved in acetone and precipitated as the naphthalene-1,5-disulfonate salt from the acetone solution. The salt, after being washed with methanol and recrystallized from water, melts at 300 C., and the yield amounts to 47% of the theoretical.

Attention is directed to our copending United States applications Serial Nos. 351,752 and 351,753, also filed on April 28, 1953, wherein we have described and claimed other dihydropyrrolo- (3.2-c)quinoline derivatives and processes for their production.

Having thus described the subject matter of this invention, what it is desired to secure by Letters Patent is:

1. As a new chemical compound, a substance chosen from the group consisting of compounds represented by the formula:

R N OH:

wherein R1 is chosen from the group consisting of hydrogen, methyl, dimethylaminoethyl, diethylaminoethyl, and benzyl; and R2, R3, R4 and R5 are chosen from the group consisting of hydrogen and at most two members chosen from the group consisting of hydroxy, methoxy, ethoxy, N-methylcarbamyl and chlorine.

2. As a new chemical compound, 4-methyl-2,3- dihydropyrrolo- (3.2-c) quinoline.

3. As a new chemical compound, 4-methy1-6- methoxy-2,3-dihydropyrrolo-(3.2-c)quinoline.

4. As a new chemical compound, 1,4-dimethyl- 2,3-dihydropyrrolo- (3.2-c) quinoline.

5. As a new chemical compound, 1,4-dimethyl- 7-hydroxy-2,3-dihydropyrrolo- (3.2-c) quinoline.

6. As a new chemical compound, 1,4-dimethyl- 8-hydroxy-2,3-dihydropyrrolo- (3.2-c) quinoline.

7. As a new chemical compound, 1,4-dimethyl- G-methoxy-2,3-dihydropyrrolo- (3.2-c) quinoline.

8. As a new chemical compound, 1,4-dimethyl- 7 -methoXy-2,3-dihydropyrrolo- (3.2-c) quinoline.

9. As a new chemical compound, 1,4-dimethyl- 8-methoxy-2,3-dihydropyrrolo- (3 .2-c) quinoline.

10. As a new chemical compound, 1,4-dimethyl- 6-ethoxy-2,3-dihydropyrrolo- (3.2-c) quinoline.

11. As a new chemical compound, 1,4-dimethyl- 8-ethoxy-2,3-dihydropyrrolo- (3.2-c) quinoline.

12. As a new chemical compound, 1,4-dimethyl- 8 N methylcarbamyl 2,3 dihydropyrrolo (3.2-c) quinoline.

13. As a new chemical compound, l-B-dimethylaminoethyl 4 -methyl 6 methoxy 2,3 dihydropyrrolo- (3.2-c) quinoline.

14. As a new chemical compound, l-B-diethylaminoethyl 4 methyl 2,3 dihydropyrrolo (3.2-c) quinoline.

15. As a new chemical compound, l-fl-die'thylaminoethyl 4 methyl 6 hydroxy 2,3 dihydropyrrolo-(3.2-c) quinoline.

16. As a new chemical compound, l-p-diethylaminoethyl 4 methyl 7 hydroxy 2,3 dihydropyrrclo- (3.2-c) quinoline.

17. As a new chemical compound, l-p-diethylaminoethyl 4 methyl 6 methoxy 2,3 dihydropyrrolo- 3.2 -c) quinoline.

18. As a new chemical compound, l-fi-diethyL- aminoethyl 4 -methyl 7 -methoxy 2,3 dihydropyrrolo- (3.2-c) quinoline.

19. As a new chemical compound, l-p-diethylamino 4 methyl 8 methoxy 2,3 dihydropyrrolo- (3.2-c) quinoline.

20. As a new chemical compound, l-B-die'thylaminoethyl 4 methyl 7,8 dimethoxy 2,3 dihydropyrrolo-(3.2-c) quinoline.

21. As a new chemical compound, l- 3-diethylaminoethyl 4 methyl 6 methoxy 9 chloro-2,3-dihydropyrrolo-(3.2-c) quinoline.

22. As a new chemical compound, l-fl-diethylaminoethyl 4 methyl 8 chloro 2,3 dihydropyrrolo- (3.2-c) quinoline.

23. As a new chemical compound, 1-benzyl-4- methyl 6 ethoxy 2,3 dihydropyrrolo (3.2- c)quinoline.

24. Process for the synthesis of 4-methyl-2,3- dihydropyrrolo-(3.2-c) quinoline compounds that comprises reacting, at an elevated temperature and in a suitable semi-polar organic solvent medium chosen from the group consisting of alcohols and phenols, a substance chosen from the group consisting of ammonia and primary amines, with a 3-B-halo-ethyl-4-halo-quinaldine, and recovering the desired reaction product from the reaction mixture.

References Cited in the file of this patent UNITED STATES PATENTS Number Name Date 2,196,776 McNally et al Apr. 9, 1940 2,650,229 Timmler et a1 Aug. 25, 1953 

1. AS A NEW CHEMICAL COMPOUND, A SUBSTANCE CHOSEN FROM THE GROUP CONSISTING OF COMPOUND REPRESENTED BY THE FORMULA: 